Actions of Two Main Metabolites of Propiverine (M-1 and M-2) on Voltage-Dependent L-Type Ca2+ Currents and Ca2+ Transients in Murine Urinary Bladder Myocytes

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Actions of Two Main Metabolites of Propiverine (M-1 and M-2) on Voltage-Dependent L-Type Ca2+ Currents and Ca2+ Transients in Murine Urinary Bladder Myocytes. / Zhu, HL; Brain, Keith; Aishima, M; Shibata, A; Young, JS; Sueishi, K; Teramoto, N.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 324, No. 1, 01.2008, p. 118-127.

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@article{0528b6037a424a628a84f591d8262183,
title = "Actions of Two Main Metabolites of Propiverine (M-1 and M-2) on Voltage-Dependent L-Type Ca2+ Currents and Ca2+ Transients in Murine Urinary Bladder Myocytes",
abstract = "The anticholinergic propiverine (1-methyl-4-piperidyl diphenylpropoxyacetate), which is used for the treatment of overactive bladder syndrome, has functionally active metabolites [M-1 (1-methyl-4-piperidyl diphenylpropoxyacetate N-oxide) and M-2 (1-methyl-4-piperidyl benzilate N-oxide)], but the site of actions of these metabolites is uncertain. Propiverine is rapidly absorbed after oral administration and is extensively biotransformed in the liver, giving rise to several active metabolites (M-1 and M-2). This study determines the effect of M-1 and M-2 on voltage-dependent nifedipine-sensitive inward Ca(2+) currents (I(Ca)) using patch-clamp techniques and fluorescent Ca(2+) imaging [after electrical field stimulation (EFS) and acetylcholine (ACh)] in the murine urinary bladder. In conventional whole-cell recording, propiverine and M-1 but not M-2 inhibited the peak amplitude of I(Ca) in a concentration-dependent manner at a holding potential of -60 mV (propiverine, K(i) = 10 microM; M-1, K(i) = 118 microM). M-1 shifted the steady-state inactivation curve of I(Ca) to the left at -90 mV by 7 mV. Carbachol (CCh) reversibly inhibited I(Ca). This inhibition probably occurred through muscarinic type 3 receptors, coupling with G-proteins, because nanomolar concentrations of 4-diphenylacetoxy-N-methyl-piperidine greatly reduced this inhibition, whereas pirenzepine or 11-([2-[(diethylamino)methyl]-1-piperdinyl]acetyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine-6-one (AF-DX 116) at concentrations up to 1 microM was almost ineffective. In the presence of M-2, the CCh-induced inhibition of I(Ca) was blocked. In fluorescent Ca(2+) imaging, M-2 inhibited EFS-induced and ACh-induced Ca(2+) transients. These results suggest that M-1 acts, at least in part, as a Ca(2+) channel antagonist (as it inhibited I(Ca)), whereas M-2 has more direct antimuscarinic actions.",
author = "HL Zhu and Keith Brain and M Aishima and A Shibata and JS Young and K Sueishi and N Teramoto",
year = "2008",
month = jan,
doi = "10.1124/jpet.107.130021",
language = "English",
volume = "324",
pages = "118--127",
journal = "Journal of Pharmacology and Experimental Therapeutics",
issn = "0022-3565",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "1",

}

RIS

TY - JOUR

T1 - Actions of Two Main Metabolites of Propiverine (M-1 and M-2) on Voltage-Dependent L-Type Ca2+ Currents and Ca2+ Transients in Murine Urinary Bladder Myocytes

AU - Zhu, HL

AU - Brain, Keith

AU - Aishima, M

AU - Shibata, A

AU - Young, JS

AU - Sueishi, K

AU - Teramoto, N

PY - 2008/1

Y1 - 2008/1

N2 - The anticholinergic propiverine (1-methyl-4-piperidyl diphenylpropoxyacetate), which is used for the treatment of overactive bladder syndrome, has functionally active metabolites [M-1 (1-methyl-4-piperidyl diphenylpropoxyacetate N-oxide) and M-2 (1-methyl-4-piperidyl benzilate N-oxide)], but the site of actions of these metabolites is uncertain. Propiverine is rapidly absorbed after oral administration and is extensively biotransformed in the liver, giving rise to several active metabolites (M-1 and M-2). This study determines the effect of M-1 and M-2 on voltage-dependent nifedipine-sensitive inward Ca(2+) currents (I(Ca)) using patch-clamp techniques and fluorescent Ca(2+) imaging [after electrical field stimulation (EFS) and acetylcholine (ACh)] in the murine urinary bladder. In conventional whole-cell recording, propiverine and M-1 but not M-2 inhibited the peak amplitude of I(Ca) in a concentration-dependent manner at a holding potential of -60 mV (propiverine, K(i) = 10 microM; M-1, K(i) = 118 microM). M-1 shifted the steady-state inactivation curve of I(Ca) to the left at -90 mV by 7 mV. Carbachol (CCh) reversibly inhibited I(Ca). This inhibition probably occurred through muscarinic type 3 receptors, coupling with G-proteins, because nanomolar concentrations of 4-diphenylacetoxy-N-methyl-piperidine greatly reduced this inhibition, whereas pirenzepine or 11-([2-[(diethylamino)methyl]-1-piperdinyl]acetyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine-6-one (AF-DX 116) at concentrations up to 1 microM was almost ineffective. In the presence of M-2, the CCh-induced inhibition of I(Ca) was blocked. In fluorescent Ca(2+) imaging, M-2 inhibited EFS-induced and ACh-induced Ca(2+) transients. These results suggest that M-1 acts, at least in part, as a Ca(2+) channel antagonist (as it inhibited I(Ca)), whereas M-2 has more direct antimuscarinic actions.

AB - The anticholinergic propiverine (1-methyl-4-piperidyl diphenylpropoxyacetate), which is used for the treatment of overactive bladder syndrome, has functionally active metabolites [M-1 (1-methyl-4-piperidyl diphenylpropoxyacetate N-oxide) and M-2 (1-methyl-4-piperidyl benzilate N-oxide)], but the site of actions of these metabolites is uncertain. Propiverine is rapidly absorbed after oral administration and is extensively biotransformed in the liver, giving rise to several active metabolites (M-1 and M-2). This study determines the effect of M-1 and M-2 on voltage-dependent nifedipine-sensitive inward Ca(2+) currents (I(Ca)) using patch-clamp techniques and fluorescent Ca(2+) imaging [after electrical field stimulation (EFS) and acetylcholine (ACh)] in the murine urinary bladder. In conventional whole-cell recording, propiverine and M-1 but not M-2 inhibited the peak amplitude of I(Ca) in a concentration-dependent manner at a holding potential of -60 mV (propiverine, K(i) = 10 microM; M-1, K(i) = 118 microM). M-1 shifted the steady-state inactivation curve of I(Ca) to the left at -90 mV by 7 mV. Carbachol (CCh) reversibly inhibited I(Ca). This inhibition probably occurred through muscarinic type 3 receptors, coupling with G-proteins, because nanomolar concentrations of 4-diphenylacetoxy-N-methyl-piperidine greatly reduced this inhibition, whereas pirenzepine or 11-([2-[(diethylamino)methyl]-1-piperdinyl]acetyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine-6-one (AF-DX 116) at concentrations up to 1 microM was almost ineffective. In the presence of M-2, the CCh-induced inhibition of I(Ca) was blocked. In fluorescent Ca(2+) imaging, M-2 inhibited EFS-induced and ACh-induced Ca(2+) transients. These results suggest that M-1 acts, at least in part, as a Ca(2+) channel antagonist (as it inhibited I(Ca)), whereas M-2 has more direct antimuscarinic actions.

U2 - 10.1124/jpet.107.130021

DO - 10.1124/jpet.107.130021

M3 - Article

C2 - 17928569

VL - 324

SP - 118

EP - 127

JO - Journal of Pharmacology and Experimental Therapeutics

JF - Journal of Pharmacology and Experimental Therapeutics

SN - 0022-3565

IS - 1

ER -